rs4821478

Positions:

• chr22-36294067-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000216181.11(MYH9):​c.3837+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,604,594 control chromosomes in the GnomAD database, including 342,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29113 hom., cov: 33)
  • Exomes 𝑓: 0.65 (313488 hom.)
• Consequence: MYH9 ENST00000216181.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.16

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-36294067-G-A is Benign according to our data. Variant chr22-36294067-G-A is described in ClinVar as [Benign]. Clinvar id is 258745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6	c.3837+25C>T		intron_variant		ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.3837+25C>T		intron_variant		1	NM_002473.6	ENSP00000216181	P1
MYH9	ENST00000685801.1	c.3900+25C>T		intron_variant				ENSP00000510688
MYH9	ENST00000691109.1	n.4132+25C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92465 AN: 152026 Hom.: 29098 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.604

GnomAD3 exomes AF: 0.588 AC: 142978 AN: 243054 Hom.: 44577 AF XY: 0.583 AC XY: 77051 AN XY: 132210

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.221

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.621

GnomAD4 exome AF: 0.648 AC: 940955 AN: 1452450 Hom.: 313488 Cov.: 43 AF XY: 0.641 AC XY: 463291 AN XY: 723056

Gnomad4 AFR exome AF: 0.524

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.518

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.663

Gnomad4 NFE exome AF: 0.690

Gnomad4 OTH exome AF: 0.610

GnomAD4 genome AF: 0.608 AC: 92519 AN: 152144 Hom.: 29113 Cov.: 33 AF XY: 0.601 AC XY: 44713 AN XY: 74376

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.645

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.382

Gnomad4 FIN AF: 0.655

Gnomad4 NFE AF: 0.688

Gnomad4 OTH AF: 0.598

Alfa AF: 0.645 Hom.: 8062

Bravo AF: 0.607

Asia WGS AF: 0.273 AC: 950 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 87% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 81. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4821478; hg19: chr22-36690113; COSMIC: COSV53395767; COSMIC: COSV53395767;